In the past decade, researcher's efforts focused at the discovery of therapeutically useful inhibitors of protein kinases have been intensified. These efforts have resulted in the identification of a variety of templates which, depending upon the nature of attached substituents, provide selective inhibition both within and across different protein kinase families. One such effort led to the discovery of pyrrolo[2,1-f][1,2,4]triazine nucleus as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold, which has been serving a core template for a variety of ATP-competitive kinase inhibitors.
Thus, the current trend of research is now focused on novel analogs of pyrrolo[2,1-f][1,2,4]triazine so as to provide potent biochemical inhibitors of the tyrosine kinase activity. There is ample literature available on synthesis of novel pyrrolo[2,1-f][1,2,4]triazine molecules.
Aqua mediated one pot facile synthesis of novel thioxo-1,2,4-triazin-5(2h)-one and [1,2,4]triazino[5,6-a]indole derivatives and their biological activities is disclosed by Harshita Sachdeva et al. in J. Chil. Chem. Soc, 57, No 4 (2012), págs: 1348-1354.
WO/2013/177983 (Yang Chunhao et al.) discloses pyrrolo[2,1-f][1,2,4]triazine compounds and their use for treating phosphatidylinositol-3 kinase related diseases such as cancer. EP2289894 (Dyckman Alaric et al.) relates to cycloalkyl, heterocyclo and heteroaryl pyrrolotriazine aniline compounds useful for treating p38 kinase-associated conditions.
Synthesis and antiproliferative activity of [1,2,4]triazino[4,3-a]indoles is reported in anticancer research 24: 3775-3780 (2004) by Paola Barraja et al.
An article titled “Discovery of pyrrolo[2,1-f][1,2,4]triazine C6-ketones as potent, orally active p38a MAP kinase inhibitors” by Dyckman A J, Li T, et al published in Bio. org Med ChemLett. 2011, Aug. 1; 21(15):4633-7 discloses preparation of Pyrrolo[2,1-f][1,2,4]triazine based inhibitors of p38a and explored functional group modifications at the C6 position and concludes that incorporation of aryl and heteroaryl ketones at this position led to potent inhibitors with efficacy in in vivo models of acute and chronic inflammation.
Another article titled “Synthesis and SAR of new pyrrolo[2,1-f][1,2,4]triazines as potent p38 alpha MAP kinase inhibitors” by Wrobleski S T et al published in Bio. Org. Med. Chem. Lett. 2008 Apr. 15; 18(8):2739-44, reports a novel series of compounds based on the pyrrolo[2,1-f][1,2,4]triazine ring system have been identified as potent p38 alpha MAP kinase inhibitors.
Yet another article titled “Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles” by Shirish A. Patil et al published in J. O. Heterocyclic chemistry volume 31, issue 4, pages 781-786, describes synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines. 1-aminopyrrole-2-carbonitrile intermediates were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO→CN conversion with either hydroxylamine-O-sulfonic acid or O-mesitylenesulfonylhydroxylamine. Cyclization of the product thus obtained with a variety of amidine reagents or, after conversion of the product to its corresponding amide followed by base-catalyzed annulation completed the synthesis of the title products.